Catherine E. Costello, Ph.D.

Funded in March, 2008: $600000 for 3 years

Autoantigens in Patients with Rheumatoid Arthritis or Antibiotic-Refractory Lyme Arthritis

Rheumatoid arthritis is the most common form of chronic inflammatory arthritis, affecting approximately 1 in 100 people. Lyme disease is the most common vector-borne infection in the United States, and arthritis is the most frequent late manifestation of the infection. Despite appropriate antibiotic therapy, a small percentage of these patients have persistent arthritis, termed antibiotic-refractory Lyme arthritis. In both diseases, it is thought that the immune system reacts against self-components (autoantigens) in affected tissue in the joint (called synovial tissue), but the identity of disease-causing autoantigens is not known in either illness.

In this grant proposal, we will attempt to identify autoantigens in patients’ synovial tissue using newly developed technology. First, improvements in mass spectrometry and the development of large computer databases, which contain sequences for most of the human genome and a number of microbial genomes, now make it possible to identify peptides presented by the immune system in patients’ synovial tissue and the proteins of origin of these peptides. Second, large protein arrays, expressing over 38,000 human cloned genes, now make it possible to identify autoantibodies to human proteins in patients’ serum and/or joint fluid. If new candidate autoantigens are identified, large panels of samples from patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis will be used to determine whether these responses are commonly found in patients with these diseases.

The identification of relevant autoantigens in rheumatoid arthritis and antibiotic-refractory Lyme arthritis would be likely to have a marked impact on the diagnosis and treatment of these diseases.

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory joint disease of unknown cause. Although the cause of Lyme arthritis is known (infection with the tick-borne spirochete Borrelia burgdorferi), despite appropriate antibiotic therapy a small percentage of these patients have persistent proliferative synovitis, termed antibiotic-refractory Lyme arthritis, which may result from infection-induced autoimmunity. RA and antibiotic-refractory Lyme arthritis share similar synovial histopathology and HLA-DR associations, but it is not known in either disease whether these HLA molecules present autoantigens that are important in disease pathogenesis.

In an effort to identify such autoantigens, we will conduct a novel and comprehensive assessment of the T cell epitopes presented in the synovial tissue of individual patients with RA or antibiotic-refractory Lyme arthritis using his or her synovial tissue as a source of HLA-DR-peptide complexes from which naturally presented peptides will be eluted, identified by mass spectrometry, and tested for reactivity with his or her peripheral blood or synovial fluid T cells. In addition, we will characterize the autoantibody profile of the same individual patients using his or her serum and/or joint fluid samples to screen large arrays that express proteins encoded by 70-80% of the human genome. Finally, candidate autoantigens, particularly those with a linked T and B cell response, will be tested using large panels of samples from patients with RA or antibiotic-refractory Lyme arthritis.

The identification of relevant autoantigens in these diseases would be likely to have a major impact on diagnosis and treatment. The determination of T and B cell responses to autoantigens might allow the development of biomarkers of disease activity. Furthermore, knowledge about pathogenic autoimmune responses could lead to the development of small molecule or tolerizing vaccines to treat these diseases.

Catherine E. Costello, Ph.D.

Dr. Costello is a Professor in the Departments of Biochemistry and Biophysics at Boston University School of Medicine, and is the founding Director of both the NIH-NCRR Mass Spectrometry Resource and the NIH-NHLBI Cardiovascular Proteomics Center at BUSM. She has served as President of the American Society for Mass Spectrometry; she is a Councilor for the American Chemical Society, a member of the US National Committee for IUPAC, the boards of the Human Proteome Organization, the Human Disease Glycomics/Proteome Initiative and the US Human Proteome Organization, and numerous editorial, review and advisory boards. Dr. Costello's research aims to refine and extend mass spectrometry methods and elucidate structure-activity relationships as they influence or reflect processes related to health, growth and development, and disease.Dr. Allen C. Steere, medical researcher and physician, is internationally recognized for his studies of Lyme disease. He currently serves as Professor of Medicine at Harvard Medical School and Director of Clinical, Translational Research in Rheumatology at Massachusetts General Hospital. In recent years, his research has focused on understanding a rare complication of Lyme arthritis called antibiotic-refractory Lyme arthritis, which is thought to result from infection-induced autoimmunity. These studies have served as a bridge to work on rheumatoid arthritis, which he is now undertaking.

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